Nasal delivery of parasiticides

ABSTRACT

A method to treat an animal in need thereof with one or more parasiticides by administering those one or more parasiticides to the nasal pharynx of the animal. A method to increase an animal&#39;s blood levels of one or more avermectin compounds/milbemycin compounds such that the blood levels of those one or more avermectin compounds/milbemycin compounds reach a maximum concentration in about 24 hours, and such that those blood levels exceed about 2 ng/ml for at least 96 hours post administration.

FIELD OF THE INVENTION

The present invention relates to a method to increase blood levels ofone or more parasiticides by administering those one or parasiticides tothe nasal pharynx of animals, including humans. In certain embodiments,Applicants' invention relates to a method to increase blood levels ofone or more macrocyclic lactone parasiticides by administering those oneor macrocyclic lactone parasiticides to the nasal pharynx of animals,including humans. In certain embodiments, Applicants' invention relatesto a method to increase blood levels of ivermectin by administeringivermectin to the nasal pharynx of animals, including humans.

BACKGROUND OF THE INVENTION

The avermectin family, of which ivermectin is a member, is a series ofvery potent antiparasitic agents which are useful against a broadspectrum of endoparasites and ectoparasites in mammals. Ivermectin isdisclosed in U.S. Pat. No. 4,199,569, issued Apr. 22, 1980 to Chabalaand Fisher. Ivermectin is a mixture, in the ratio of approximately 80:20of 22,23-dihydro C-076 B1a and B1b.

Ivermectin is a member of a family of compounds identified asavermectins. The basic avermectin compounds are isolated from thefermentation broth of the microorganism Streptomyces avermitilis. Suchcompounds are described in U.S. Pat. No. 4,310,519. In addition, certainderivatives of these basic fermentation products have been prepared.Some of the avermectins contain a 22,23-double bond. This may beselectively reduced to prepare the ivermectin compounds discussed above.In addition, the avermectins possess a disaccharide moiety at the13-position consisting of the a-L-oleandrosyl-a-L-oleandrosyl group. Oneor both of these saccharide groups may be removed as described in U.S.Pat. No. 4,206,205. The thus produced aglycone derivatives have ahydroxy group at the 13-position. This group may be removed to form the13-deoxy compound as described in U.S. Pat. Nos. 4,171,314 and4,173,571. On the avermectin compounds and derivatives are severalhydroxy groups which may be acylated as described in U.S. Pat. No.4,201,861.

A series of compounds identified as milbemycin compounds have the same16 membered macrocyclic ring as do the avermectin compounds, althoughthey do not have the disaccharide moiety and also differ in the natureof other substituent groups. These compounds are disclosed in U.S. Pat.No. 3,950,360 and they also would be expected to benefit in theirspectrum of activity by the instant process and formulations.

Various medicaments, including avermectin compounds/milbemycincompounds, have traditionally been administered orally or by injection(subcutaneous, intramuscular) to animals, including humans. In thecontext of feedstock animals, i.e. meat-producing animals, suchavermectin compounds/milbemycin compounds are sometimes added to theanimals' food. Such oral administration, however, does not effectivelydeliver the proper dosage to each and every animal. Significantly,animals that are sick often do not eat or drink properly. These sickanimals, however, may be in greatest need such medicaments, includingone or more avermectin compounds/milbemycin compounds.

Administration of avermectin compounds/milbemycin compounds to feedstockanimals via intramuscular injection is an effective, but undesirableroute of dosing. This route requires sterile procedures that can bedifficult to maintain under field conditions. Intramuscular injectionsoften result in tissue bruising, injection site lesions and concomitantproduct loss post-mortem.

Subcutaneous injection can be difficult to administer and can causeswelling at the injection site. Furthermore, subcutaneous injections maybe given intramuscularly by mistake and reduce the effectiveness of theactive compound. Animals/humans do not like injections and can moveduring the administration causing the needle to break off at theinjection site. This creates a hazard for the animal/human and acontaminant in the food chain.

What is needed is a method to administer one or more parasiticides toanimals, including humans, where that method is both cost-effective andtime-effective.

SUMMARY OF THE INVENTION

Applicants' invention includes a method to treat an animal in needthereof with one or more parasiticides by administering those one ormore parasiticides to the nasal pharynx of the animal. Applicants'invention further includes a method to increase blood levels of one ormore avermectin compounds/milbemycin compounds such that the bloodlevels of those one or more avermectin compounds/milbemycin compoundsreach a maximum concentration in about 24 hours, and such that thoseblood levels exceed about 2 ng/ml for at least 96 hours postadministration.

BRIEF DESCRIPTION OF THE DRAWINGS

The invention will be better understood from a reading of the followingdetailed description taken in conjunction with the drawings in whichlike reference designators are used to designate like elements, and inwhich:

FIG. 1 is a graph showing serum levels of ivermectin as a function oftime after administering the ivermectin to the nasal pharynx.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

Applicants' invention will be described as embodied in a method toincrease serum levels of ivermectin in feedstock animals. The followingdescription of Applicant's nasal delivery method is not meant, however,to limit Applicant's invention to administering ivermectin tomeat-producing animals, as the invention herein can be applied generallyto administering one or more avermectin compounds/milbemycin compoundsto animals, including humans.

The macrocyclic lactones are natural fermentation products ofsoil-dwelling Streptomycetes bacteria. They consist of two sub groups,the avermectins and the milbemycins. Their basic chemical structureconsists of a macrocyclic lactone, a spiroketal addition fused from C-17to C-25 and a hexahydrobenzofiran unit fused from C-2 to C-8. Theavermectins also include an oxy disaccharide substituted at positionC-13 whereas this position is not substituted in the milbemycins.Several different alkyl groups can be substituted at position C-25 inboth sub groups. The basic structures of the two can be superimposed oneach other. As a result the avermectins may be described as glycosylatedmilbemycins. Conversely the milbemycins may be described asdeglycosylated avermectins.

The macrocyclic lactones have broad spectrum activities against a widerange of nematodes and arthropods and their effectiveness against bothendo- and ectoparasites has given rise to the name endectocides. Theyare highly effective at low doses (micrograms per kilogram of bodyweight) against most of the economically important nematodes offood-producing livestock and have a wide margin of safety. Some of themhave zero meat and milk withdrawal times.

In the United States, there are, currently, six commercially availablemacrocyclic lactones: Ivermectin, Eprinomectin, Moxidectin, Selamectin,Doramectin and Milbemycin. The macrocyclic lactones are not effectiveagainst trematodes and cestodes. To compensate for this, Applicants'method includes administering to the nasal pharnyx of animals, includinghumans, one or more avermectins/milbemycins in combination with one ormore other anthelmintic drugs. In certain embodiments, Applicants'method includes administering via the nasal pharnyx ivermectin incombination with Clorsulon.

Production of avermectins from natural fermentation of Streptomycesavermitilis results in a mixture of eight slightly different components.They are designated A1a, A1b, A2a, A2b, B1a, B1b, B2a and B2b. Of these,only A2a, B1a and B2a are produced in significant amounts duringfermentation. The B1 homologs are the most potent and also have thebroadest spectrum of activity, at least among the nematodes.

The a and b homologs have almost identical activities and because a isproduced in much greater amounts than b, the terminology used todescribe the avermectins is often shortened to omit separate referenceto the a and b homologs and the more abundant a component is the onlyone shown in structural drawings. This is illustrated below in referenceto ivermectin.

Ivermectin terminology Common description Actual components 22, 23dihydro(xy) 22, 23 dihydro(xy) avermectin B1a (>80%) + avermectin B1 22,23 dihydro(xy) avermectin B1b (<20%)

Milbemycins result from fermentation of Streptomyces hygroscopicus andStreptomyces cyaneogriseus. They are also produced as mixtures ofslightly different components similar to the avermectins.

The macrocyclic lactones appear to act by interacting withglutamate-gated chlorine channels in muscle membranes. This interactionopens these chloride channels allowing chlorine ions to pass through andalter muscle function resulting in paralysis. The specific sites ofaction may include not only somatic muscles but also pharyngeal musclessince experiments with ivermectin using Haemonchus contortus andTrichostrongylus colubriformis have shown more potent inhibition ofpharyngeal pumping than motility. Although most of the experiments havebeen done with ivermectin, it is generally believed that all macrocycliclactones will share the same mode of action.

The macrocyclic lactones are expensive. Nevertheless, these macrocycliclactones have gained wide acceptance by veterinarians, horse owners,farmers and the dog and cat owning public. Prior art methods ofadministering ivermectin vary considerably with respect to effectivedelivery and ease of use. Comparing subcutaneous injection of ivermectinwith topical application of ivermectin, administration by injectionrealizes a cost efficiency with a lower time efficiency.

The following example is presented to further illustrate to personsskilled in the art how to make and use the invention and to identifypresently preferred embodiments thereof. This example is not intended,however, as a limitation upon the scope of the invention, which isdefined only by the appended claims.

EXAMPLE

To study the dose/response efficacy of nasal administration ofmacrocyclic lactone parasicides, three (3) beef steers of mixed breedingwere used to evaluate three treatments. These three treatments were:

Treatment 1 500 milligrams of ivermectin in 5 ml propylene glycol; 1 mlof mixture administered to nasal pharnyx at level of about 248 μg/kgbody weight; Treatment 2 1,000 milligrams of ivermectin in 5 mlpropylene glycol; 1 ml of mixture administered to nasal pharnyx at levelof about 409 μg/kg body weight; Treatment 3 1,500 milligrams ofivermectin in 5 ml propylene glycol; 1 ml of mixture administered tonasal pharnyx at level of about 872 μg/kg body weight;

Treatments were applied and cattle were bled via jugular venipuncture at0, 6, 24, 48, and 96 hours post-dosing.

TABLE I 0 Hours 6 Hours 24 Hours 48 Hours 96 Hours Treatment 1 0.19 5.8715.24 11.22 7.58 Treatment 2 0.21 6.58 24.48 19.71 13.88 Treatment 30.22 22.51 40.79 30.53 19.38

Table I recites serum levels of ivermectin, in nanograms per milliliter,for the three treatments recited above at 0, 6, 24, 48, and 96 hourspost dosing by nasal administration. Each treatment included deliveringa 1 ml mixture comprising ivermectin and propylene glycol to the nasalpharnyx of the animal.

Referring now to FIG. 1, graph 100 recites the data of Table I. Curve110 shows the serum concentration of ivermectin over time resulting fromTreatment 1. Nasal administration of ivermectin in propylene glycol at adosage of about 248 micrograms per kilogram body weight gave a maximumserum level C_(MAX(1)) of about 15 nanograms of ivermectin per ml ofblood at about 24 hours post-dosing.

Curve 120 shows the serum concentration of ivermectin over timeresulting from Treatment 2. Nasal administration of ivermectin inpropylene glycol at a dosage of about 409 micrograms per kilogram bodyweight gave a maximum serum level C_(MAX(2)) of about 24 nanograms ofivermectin per ml of blood at about 24 hours post-dosing.

Curve 130 shows the serum concentration of ivermectin over timeresulting from Treatment 3. Nasal administration of ivermectin inpropylene glycol at a dosage of about 872 micrograms per kilogram bodyweight gave a maximum serum level C_(MAX(3)) of about 41 nanograms ofivermectin per ml of blood at about 24 hours post-dosing.

In a publication entitled “Comparison of pharmokinetic profiles ofdoramectin and ivermectin pour-on formulations in cattle,” VeterinaryParasitology, 81, 47-55 (1999), Gayrard, Alvinerie, and Toutain reportthat the clinical efficacy of parasiticides, including ivermectin,depends upon the parasites' systemic exposure to the parasiticide. Id.at 54. Gayrard, Alvinerie, and Toutain further report that serum levelsof ivermectin in cattle in excess of 2 ng/ml are sufficient to protectthe animal against reinfestation of most parasites. Id.

As those skilled in the art will appreciate, when an animal is infestedwith one or more parasite species, a rapid increase in serum level ofivermectin is advantageous to rid the animal of those one or moreparasites. In addition, prolonged serum levels exceeding about 2 ng ml⁻¹are advantageous to prevent reinfestation. Table I and FIG. 1 clearlyshow that Applicants' method produced the maximum serum level ofivermectin, C_(MAX), at about 24 hours post dosing for all threetreatments discussed above. Table I and FIG. 1 further show thatApplicants' method results in serum levels of ivermectin exceeding 2 ngml⁻¹ for well in excess of 96 hours.

Levels 140 and 150 comprise C_(MAX) blood levels obtained using priorart methods, namely by administering ivermectin by subcutaneousinjection and topical application, respectively. Gayrard, Alvinerie, andToutain administered ivermectin topically at a dosage of 500 microgramsper kilogram body weight. This article reports a C_(MAX) for ivermectinof 12.2 ng/ml which occurred 3.4 days after administration. Referringagain to FIG. 1, Level 150 on graph 100 graphically depicts the C_(MAX)reported by Gayrard, Alvinerie, and Toutain.

As curve 110 shows, Applicants' nasal administration of ivermectin at adosing of about 248 micrograms per kilogram in Treatment 1 resulted in aC_(MAX(1)) of greater than 15 ng/ml which occurred about 1 day afteradministration. Thus, comparing Applicants' nasal administration ofivermectin with a prior art topical administration, Applicants' methodusing half the dosage of ivermectin nevertheless achieves a highermaximum serum level in about one third of the time. Those skilled in theart will appreciate that Applicants' nasal delivery of ivermectinachieves a higher C_(MAX) at a faster rate. Those skilled in the artwill appreciate that Applicants' method is clearly more cost-effectiveand time-effective than prior art topical administration.

In an article entitled “Comparing Pharmacokinetics of IVOMEC(ivermectin) 1% Injection and DECTOMAX (doramectin) 1% Injectable inCattle,” Merial Veterinary Bulletin, TSB-8-98031FTB (1998), JoanneBicknese reports a C_(MAX) serum level of ivermectin of about 30 ng/mlafter injection of a dose of about 200 micrograms of ivermectin perkilogram of bodyweight. Bicknese further reports that the C_(MAX) leveloccurred about 3-4 days after administration. Level 140 on graph 100graphically depicts Bicknese's reported C_(MAX).

As those skilled in the art will appreciate, a parenteral ivermectinformulation must necessarily be sterilized prior to administration.Because ivermectin is subject to decomposition at autoclavetemperatures, a parenteral ivermectin formulation must be sterilizedusing other techniques. U.S. Pat. No. 4,853,372 teaches sterilizing aparenteral ivermectin formulation using membrane filtration.

Comparing Applicants' nasal administration of ivermectin with prior artparenteral administration methods, Applicants' nasal administrationgives a C_(MAX) in a shorter time period, and does not require that asterile ivermectin formulation be prepared, does not require that theivermectin formulation be packaged using aseptic methods, and does notrequire that the ivermectin formulation be administered using steriletechniques. In addition, Applicants' nasal administration does notinclude the risk that a needle may inadvertently remain in the animalafter administration. Therefore, those skilled in the art willappreciate that Applicants' nasal administration of ivermectin is at theleast more time-efficient than prior art parenteral administration, andis likely also more cost-efficient.

While the preferred embodiments of the present invention have beenillustrated in detail, it should be apparent that modifications andadaptations to those embodiments may occur to one skilled in the artwithout departing from the scope of the present invention as set forthin the following claims.

We claim:
 1. A method to treat an animal infested with one or moreparasite species with a parasiticide comprising the steps of: preparinga formulation consisting of said parasiticide and propylene glycol;delivering a therapeutically effective amount of said formulation to theanimal's nasal pharynx.
 2. The method of claim 1, wherein saidparasiticide comprises ivermectin.
 3. The method of claim 2, whereinsaid ivermectin is administered to said animal at a dosage of about 250micrograms per kilogram body weight.
 4. The method of claim 2, whereinsaid ivermectin is administered to said animal at a dosage of about 400micrograms per kilogram body weight.
 5. The method of claim 2, whereinsaid ivermectin is administered to said animal at a dosage of about 870micrograms per kilogram body weight.
 6. A method to increase bloodlevels of a macrocyclic lactone parasiticide, comprising the steps of:preparing a formulation consisting of said parasiticide and propyleneglycol; administering said formulation to said animal via the nasalpharynx.
 7. The method of claim 6, wherein said macrocyclic lactoneparasiticide comprises an avermectin.
 8. The method of claim 7, whereinsaid avermectin comprises ivermectin.
 9. The method of claim 8, whereinsaid mixture of said ivermectin and said propylene glycol is notsterilized.
 10. The method of claim 9, further comprising the steps of:mixing about 500 milligrams of ivermectin in about 5 ml of propyleneglycol; and administering about 1 ml of said mixture to the nasalpharynx of said animal.
 11. The method of claim 9, further comprisingthe steps of: mixing about 1,000 milligrams of ivermectin in about 5 mlof propylene glycol; and administering about 1 ml of said mixture to thenasal pharynx of said animal.
 12. The method of claim 9, furthercomprising the steps of: mixing about 1,500 milligrams of ivermectin inabout 5 ml of propylene glycol; and administering about 1 ml of saidmixture to the nasal pharynx of said animal.
 13. A method to treat ananimal infested with one or more parasite species with a parasiticide,comprising the steps of: preparing a formulation consisting ofivermectin and propylene glycol; administering said ivermectin to theanimal's nasal pharynx at a dosage of about 250 micrograms per kilogrambody weight, wherein the maximum serum level off ivermectin occurs about24 hours after said nasal administration, and wherein said maximum serumlevel is about 15 ng ml⁻¹.